Here, by using BDC12-4.1 Tg mice, we found that: a) few InsB:9-23-specific CD4+ T cells escape negative selection and expand in the periphery, b) most peripheral BDC12-4.1 T cells are already differentiated into Teff or Treg, c) most cells that respond to InsB:9-23 peptide stimulation produce proinflammatory cytokines and d) under in vitro polarization conditions, peripheral BDC12-4.1 cells can be efficiently grown into phenotypic Treg (Foxp3+) cells, however, they do not protect recipient NOD mice from diabetes development upon adoptive transfer. Here, CD4 is linked to diabetes mellitus.